SUMMARY The proposed research examines the potential benefits of non-invasive repetitive transcranial magnetic stimulation (rTMS) to behavior and language neurocircuit in patients with Primary Progressive Aphasia (PPA), usually an aphasic variant of Alzheimer's disease and related disorders (ADRD). A long-term goal of the research program is to deploy rTMS interventions for treatment of PPA. The proposal builds upon preliminary evidence showing that rTMS to dorsolateral prefrontal cortex improves language abilities in patients with PPA. The first aim is to replicate and extend the effects of rTMS on language in PPA. The second aim is to assess these effects in different subtypes of PPA and determine which subtype or subtypes are more likely to benefit from rTMS to dorsolateral prefrontal cortex. Training for these aims will develop the candidate's expertise in using rTMS and neuropsychological tools for clinical research in patients with PPA. Short-term goals include obtaining expertise in language assessments and longitudinal analytic methods that will further the candidate's long-term goal of assessing the efficacy of rTMS to induce durable effects in PPA. The third aim is to examine the neural mechanism of action of rTMS by measuring the effects of rTMS on functional connectivity of the brain's language network. Training for this aim will extend the candidate's expertise beyond imaging brain networks into modulating them for clinical benefits in PPA. Training for this aim will additionally develop the candidate's expertise in morphometric analyses to quantify and control for the effect of gray and white matter loss in PPA. All aims will be obtained by new data collected in the proposed project. Training available at Massachusetts General Hospital and Harvard Medical School community allows access to resources and mentors and advisors in the many techniques necessary to the aims of the candidate's training and career goals. rTMS over the dorsolateral prefrontal cortex will be administered in a single session and in consecutive 10 sessions. Language and other cognitive abilities will be measured with neuropsychological assessments. The language network functional connectivity will be measured using resting-state functional magnetic resonance imaging (rsfMRI). The brain volume and white matter integrity will be measured with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Using longitudinal data, the transient and durable effects of TMS on behavior and language network over time will be assessed. The relationship of rTMS-induced changes in language with changes in brain functional connectivity will be examined. If rsfMRI proves to be a reliable measure of neural change, it may prove to be a biomarker for predicting TMS treatment responsiveness. Completion of the aims will enhance our understanding of the behavioral and neuromodulatory mechanisms of rTMS and inform future trials that optimize treatments for PPA, in line with the NIDCD strategic plans on developing novel intervention strategies to improve outcomes in PPA.